PDBsum entry 3kex

Transferase

PDB id: 3kex

Contents

Protein chain

292 a.a. *

Ligands

ANP ×2

Metals

_MG ×2

Waters ×30

* Residue conservation analysis

PDB id:

3kex

Name:

Transferase

Title:

Crystal structure of the catalytically inactive kinase domain of the human epidermal growth factor receptor 3 (her3)

Structure:

Receptor tyrosine-protein kinase erbb-3. Chain: a, b. Fragment: unp residues 698-1019. Synonym: c-erbb3, tyrosine kinase-type cell surface receptor her3. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb3, erbb3/her3, her3. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.80Å R-factor: 0.243 R-free: 0.283

Authors:

N.Jura,Y.Shan,X.Cao,D.E.Shaw,J.Kuriyan

Key ref:

N.Jura et al. (2009). Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Proc Natl Acad Sci U S A, 106, 21608-21613. PubMed id: 20007378 DOI: 10.1073/pnas.0912101106

Date:

26-Oct-09 Release date: 22-Dec-09

Protein chains

P21860  (ERBB3_HUMAN) -  Receptor tyrosine-protein kinase erbB-3 from Homo sapiens

Seq: 1342 a.a.

Struc: 292 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.0912101106

Proc Natl Acad Sci U S A 106:21608-21613 (2009)

PubMed id: 20007378

Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.

N.Jura, Y.Shan, X.Cao, D.E.Shaw, J.Kuriyan.

ABSTRACT

The kinase domain of human epidermal growth factor receptor (HER) 3/ErbB3, a member of the EGF receptor (EGFR) family, lacks several residues that are critical for catalysis. Because catalytic activity in EGFR family members is switched on by an allosteric interaction between kinase domains in an asymmetric kinase domain dimer, HER3 might be specialized to serve as an activator of other EGFR family members. We have determined the crystal structure of the HER3 kinase domain and show that it appears to be locked into an inactive conformation that resembles that of EGFR and HER4. Although the crystal structure shows that the HER3 kinase domain binds ATP, we confirm that it is catalytically inactive but can serve as an activator of the EGFR kinase domain. The HER3 kinase domain forms a dimer in the crystal, mediated by hydrophobic contacts between the N-terminal lobes of the kinase domains. This N-lobe dimer closely resembles a dimer formed by inactive HER4 kinase domains in crystal structures determined previously, and molecular dynamics simulations suggest that the HER3 and HER4 N-lobe dimers are stable. The kinase domains of HER3 and HER4 form similar chains in their respective crystal lattices, in which N-lobe dimers are linked together by reciprocal exchange of C-terminal tails. The conservation of this tiling pattern in HER3 and HER4, which is the closest evolutionary homolog of HER3, might represent a general mechanism by which this branch of the HER receptors restricts ligand-independent formation of active heterodimers with other members of the EGFR family.

Selected figure(s)

Figure 4.
Analysis of the concatenated HER3 and HER4 kinase domains in the crystal lattices. (A) Pattern of kinase monomer interactions observed in the crystal lattices of the kinase domains of HER3 and inactive HER4 (PDB ID code 3BBW). The C-terminal tail exchanging dimers are propagated through the N-lobe dimer interface. JM refers to portion of the juxtamembrane segment. (B) Detailed view of the HER3 and HER4 N-lobe dimers. Hydrophobic residues are shown in stick representation. (C) Empirical estimates of binding free energy of HER3 and HER4 N-lobe homodimers using conformations obtained from all-atom molecular dynamics simulations. (D) Comparison between the C-terminal tail interaction with the C-lobe in the HER3 kinase domain dimer and the HER4 kinase domain dimer (PDB ID code 3BBW) and interaction of Mig6/segment 1 with the C-lobe of the EGFR kinase domain (PDB ID code 2RFE).

Figure 5.
Model for oligomerization of the kinase domains of HER3 and inactive HER4 at the plasma membrane. (A) Flexible C-terminal tail/C-lobe interaction creates a possibility for the formation of branched HER3 or inactive HER4 oligomers, resulting in a 2D mesh. (B) Empirical estimates of binding free energy of the HER3/HER4 N-lobe homodimer, calculated using conformations obtained from an all-atom molecular dynamics simulation.

Figures were selected by an automated process.